From time to time in the past, there have been efforts made to suppress tumor growth by using cytotoxic drugs linked to tumor specific antibodies as a form of cancer chemotherapy. The theory is that the antibodies would selectively transport, or deliver, the drug to the target tumor site where the cytotoxic agent would kill the tumor. However, in actual practice, it has been found that it frequently occurs that if tumor specific antibodies are linked to cytotoxic drugs, either the activity of the drug is hindered, or the activity of the antibody is hindered, or both are hindered. Thus, the net effect of the linking, or bonding of the two agents together, is that neither is fully effective.
In addition, it has been found that many of the products obtained by a direct bonding, or linkage, between a cytotoxic drug and tumor specific antibodies, results in the formation of compositions of matter which are pharmaceutically unacceptable in that they are insoluble in traditional pharmaceutical diluents, making the actual use of the composition in treatments, particularly parenteral injections, difficult if not impossible.
Additionally, in the past, attempts at linkage of cytotoxic drugs to tumor specific antibodies, have encountered difficulties in selection of the cytotoxic agent. In order to have a successful and useful composition, one must select a cytotoxic agent which is relatively non-toxic when bound or linked, but only becomes toxic in its free form after transport to the site of the malignant tumor, presumably where enzymes digest a portion of the molecule releasing the toxic agent to kill the tumor.
For examples of bonding of cytotoxic agents directly to antibodies, see Miner, et al., U.S. Pat. No. 3,803,302, Sela, U.S. Pat. No. 4,093,607, and Yoshikumi, U.S. Pat. No. 4,315,851. For an example of indirect linkage, that is, where the cytotoxic drug and the tumor specific antibody are linked, but not directly linked to each other, that is linked through an intermediate molecule, see Rowland, et al. (1975), Suppression of Tumor Growth in Mice By a Drug Antibody Conjugate Using a Novel Approach to Linkage. Nature 255:487-488. However, as heretofore mentioned, the direct linkage approach of the cited United States Letters Patents, inherently involves problems because of the strong likelihood of decreased effectiveness of either the tumor specific antibody, or the cytotoxic agent, or both. The indirect technique of Rowland et al. employs p-phenylenediamine mustard as the cytotoxic drug. The results he achieves show inconsistency, some difficulty in obtaining binding of the drug to intermediate carrier, and demonstrates results only in tissue cultures.
In contrast to the prior art, and the problems of the prior art mentioned above, the applicant has discovered a linking technique in combination with a specific cytotoxic amine agent, which when employed, allows a tumor specific antibody and the cytotoxic amine-containing agent to be indirectly linked together by both being linked to a common carrier, without being specifically linked to each other. The result is that the tumor specific activity of the antibody and the pharmacological activity of the cytotoxic amine-containing agent are not interferred with in any significant manner by the presence of the other agent, or the presence of the linked carrier. Also, in contrast to the Rowland technique, the present invention utilizes a cytotoxic agent which is easy to work with, is commonly available, and, when employed in the present invention, shows definite positive results in living organisms as opposed to mere tissue culture testing.
It is therefore a primary objective of the present invention to provide an immunochemotherapy process and composition which is effective against malignant tumors.
Another object of the present invention is to provide an immunochemotherapy composition which is water soluble, which has a cytotoxic amine-containing agent, and a tumor specific antibody, both linked to a common carrier molecule without each of the agents being linked directly to each other, such that they are both freely available; that is, the antibody and the cytotoxic amine are available each to provide their specific activity, but each without interference from the other.
An additional specific object of the present invention is to provide an immunochemotherapy composition which employs arsanalic acid as the cytotoxic amine-containing agent.
A still further objective of the present invention is to provide a carrier molecule which is capable of reacting with arsanilic acid as the cytotoxic amine-containing agent, and also capable of reacting with a tumor specific antibody, such that both can be linked to the carrier molecule to provide a composition of matter which is water soluble.
A yet further objective of the present invention is to provide a composition of matter which is capable of parenteral injection (i.e., intravenous, intraperitoneal, intralesional) to allow delivery of a cytotoxic agent to a malignant tumor site.
Another objective of the present invention is to provide a method and manner in which arsanilic acid may be linked as a cytotoxic amine-containing agent to a water soluble intermediate carrier molecule which is the reaction product of polyglutamic acid and a carbodiimide.
Still another objective is to provide an indirect linking of toxic agent and antibody so that larger amounts of toxic agent can be bound per antibody molecule, without affecting antibody activity.
A still further objective of the present invention is to provide a method for delivering to a specific tumor site of a host organism, a cytotoxic drug agent in a manner in which the agent appears to be relatively non-toxic during transport or delivery, and primarily becomes toxic at the malignant tumor site.
The method and manner of accomplishing each of the above objectives, as well as others, will be apparent to those skilled in the art from the detailed description of the invention which follows hereinafter.